Murine colitis treated with multitargeted tyrosine kinase inhibitors

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Jennifer Leslie Knod1, Kelly Crawford1, Mary Dusing1

  • 1Peña Colorectal Center, Division of Pediatric General & Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

The Journal of Surgical Research
|November 2, 2015
PubMed
Abstract

Insights

Receptor tyrosine kinase inhibitors suppressed VEGF/VEGFR in a colitis model but did not reduce angiogenesis, indicating other pathways may be involved. Disease severity and weight loss were observed in treated mice.

Area of Science:

  • Gastroenterology
  • Oncology
  • Pharmacology

Background:

  • Angiogenesis is a key factor in various diseases, including inflammatory bowel disease.
  • Vascular endothelial growth factor (VEGF) and angiogenesis are elevated in inflammatory bowel disease.
  • Targeting VEGF and angiogenesis offers a potential therapeutic strategy.

Purpose of the Study:

  • To investigate the efficacy of receptor tyrosine kinase inhibitors (RTKIs) in suppressing angiogenesis and improving disease severity in a murine model of colitis.
  • To assess the impact of RTKIs targeting VEGFR and PDGFR on angiogenesis and inflammation.

Main Methods:

  • Dextran sodium sulfate (DSS)-induced colitis model in mice.
  • Administration of RTKIs (sorafenib, sunitinib, axitinib) via oral gavage.
  • Assessment of inflammation scores, microvessel density (MVD), and gene expression of key angiogenic factors (VEGF, VEGFR, PDGF, PDGFR, Ang-2, EGFR).

Main Results:

  • DSS treatment increased inflammation and MVD, but these were similar between DSS-only and RTKI-treated groups.
  • RTKI treatment significantly decreased VEGFR expression and showed a trend towards decreased VEGF gene expression.
  • No significant changes were observed in PDGF/PDGFR pathways or alternative angiogenic pathways (Ang-2, EGFR).
  • Unexpected weight loss occurred in RTKI-treated groups.

Conclusions:

  • The study confirms the link between inflammation and MVD in colitis.
  • While RTKIs suppressed the VEGF/VEGFR pathway, a reduction in colonic MVD was not observed, suggesting other angiogenic pathways may compensate.
  • Vehicle choice and mouse strain can influence outcomes in DSS colitis models.
Keywords:
AngiogenesisColitisInflammatory bowel diseaseReceptor tyrosine kinase inhibitorsVEGF

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